In the last decade a number of peptides have been isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum). Exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma suspectum, and this peptide shares 52% homology with GLP-1(7-37) in the overlapping region. Exendin-4 is a potent GLP-1 receptor agonist which has been shown to stimulate insulin release and ensuing lowering of the blood glucose level when injected into dogs. The group of exendin-4(1-39), certain fragments thereof, analogues thereof and derivatives thereof, are potent insulinotropic agents.
Many diabetes patients particularly in the type 2 diabetes segment are subject to so-called “needle-phobia”, i.e. a substantial fear of injecting themselves. In the type 2 diabetes segment most patients are treated with oral hypoglycaemic agents, and since GLP-1 compounds and exendin-4 compounds are expected to be the first injectable product these patients will be administered, the fear of injections may become a serious obstacle for the widespread use of the clinically very promising compounds. Thus, there is a need to develop new compounds which can be administered less than once daily, e.g. once every second or third day preferably once weekly, while retaining an acceptable clinical profile. Optionally via pulmonal or nasal administration.
Exendin-4 is chemically labile due to Met14 oxidation and Asn28Gly29 deamidation. One object of the present invention is to provide a chemically stable derivative of exendins and analogues thereof. One object of the invention is to provide a long acting ie. having an administration regimen as described above—derivative of exendin or analogues thereof.